scholarly journals Musashi2 contributes to the maintenance of CD44v6+ liver cancer stem cells via notch1 signaling pathway

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Xiju Wang ◽  
Ronghua Wang ◽  
Shuya Bai ◽  
Si Xiong ◽  
Yawen Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Liver Cancer ◽  
Tissue Microarray ◽  
Migration And Invasion ◽  
Liver Cancer Stem Cells ◽  
Notch1 Signaling ◽  
And Function

Abstract Background Liver cancer stem cells (LCSCs) contribute to hepatocellular carcinoma (HCC) development, metastasis, and drug resistance. MSI2 and Notch1 signaling are involved in the maintenance of CSCs. However, it is unknown whether MSI2 and Notch1 are involved in the maintenance of CD44v6+ LCSCs. Therefore, we investigated the clinical significance and function of MSI2 and its relationship with Notch1 signaling in the maintenance of stemness properties in CD44v6+ LCSCs. Methods The expression of MSI2 and CD44v6 were detected by fresh specimens and a HCC tissue microarray. The tissue microarray containing 82 HCC samples was used to analyze the correlation between CD44v6 and MSI2. CD44v6+/− cells were isolated using microbeads sorting. We explored the roles of MSI2 and Notch1 signaling in CD44v6+ LCSCs by sphere formation assay, transwell assay, clone formation assay in vitro, and xenograft tumor models in vivo. A Notch RT2 PCR Array, Co-immunoprecipitation, and RNA-immunoprecipitation were used to further investigate the molecular mechanism of MSI2 in activating Notch1 signaling. Results Here, we found MSI2 expression was positively correlated with high CD44v6 expression in HCC tissues, and further correlated with tumor differentiation. CD44v6+ cells isolated from HCC cell lines exhibited increased self-renewal, proliferation, migration and invasion, resistance to Sorafenib and tumorigenic capacity. Both MSI2 and Notch1 signaling were elevated in sorted CD44v6+ cells than CD44v6- cells and played essential roles in the maintenance of stemness of CD44v6+ LCSCs. Mechanically, MSI2 directly bound to Lunatic fringe (LFNG) mRNA and protein, resulting in Notch1 activation. Conclusions Our results demonstrated that MSI2 maintained the stemness of CD44v6+ LCSCs by activating Notch1 signaling through the interaction with LFNG, which could be a potential molecular target for stem cell-targeted therapy for liver cancer.

scholarly journals Long noncoding RNA HULC accelerates the growth of human liver cancer stem cells by upregulating CyclinD1 through miR675-PKM2 pathway via autophagy

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Chen Wang ◽  
Xiaoxue Jiang ◽  
Xiaonan Li ◽  
Shuting Song ◽  
Qiuyu Meng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Liver Cancer ◽  
Human Liver ◽  
Noncoding Rna ◽  
Liver Cancer Stem Cells ◽  
Huh7 Cells ◽  
Human Liver Cancer

Abstract Background The functions of HULC have been demonstrated in several cancers. However, its mechanism has not been elucidated in human liver cancer stem cells. Methods Liver cancer stem cells were isolated from Huh7 cells; gene infection and tumorigenesis test in vitro and in vivo were performed. Results We demonstrate that HULC promotes growth of liver cancer stem cells in vitro and in vivo. Mechanistically, HULC enhances the expression of Sirt1 dependent on miR675 and then induces the cellular autophagy through Sirt1. HULC enhances CyclinD1 and thereby increases pRB and inhibited P21 WAF1/CIP 1 via autophagy-miR675-PKM2 pathway in human liver cancer stem cells. Ultimately, our results demonstrate that CyclinD1 is required for the oncogenic functions of HULC in liver cancer stem cells. Conclusions It reveals the key molecular signaling pathways for HULC and provides important basic information for finding effective tumor therapeutic targets based on HULC.

A novel regulatory loop miR-101/ANXA2/EGR1 mediates malignant characteristics of liver cancer stem cells

2020 ◽  
Author(s):  
Sai Ma ◽  
Junping Cheng ◽  
Haiyan Wang ◽  
Ningling Ding ◽  
Feng Zhou ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Liver Cancer ◽  
Critical Role ◽  
Migration And Invasion ◽  
Liver Cancer Stem Cells ◽  
In Vivo Experiments ◽  
Regulatory Loop

Abstract Increasing evidence suggests that liver cancer stem cells (LCSCs) are the cellular determinants that promote tumor recurrence and metastases. Aberrantly expressed miRNAs were identified in LCSCs and found to play a significant role in modulating biological characteristics of LCSCs. In this study, we implemented miRNA microarrays in CD133+ LCSCs and found miR-101 expression was downregulated. Increasing miR-101 expression repressed the metastasis and tumorigenic potential in LCSCs. Further investigations showed that ANXA2 was a novel target of miR-101. And we revealed that ANXA2 plays a critical role in acceleration of cell cycle and enhancing the migration and invasion abilities of LCSCs. Elevated ANXA2 increased activation of extracellular signal-regulated kinase (ERK) which regulated SOX2 and cell cycle-related kinases. Moreover, ERK phosphorylation inhibited the expression of early growth response 1 (EGR1) which in turn restrained the transcription of miR-101. In vivo experiments, overexpression of miR-101 produced potent inhibitory effects on the growth of LCSCs xenograft tumors as well as ANXA2 knockdown. Taken together, our findings suggest a novel regulatory loop miR-101/ANXA2/EGR1 in LCSCs and may serve as potential therapeutic targets in liver cancer.

scholarly journals MicroRNA-28-5p Regulates Liver Cancer Stem Cell Expansion via IGF-1 Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Qing Xia ◽  
Tao Han ◽  
Pinghua Yang ◽  
Ruoyu Wang ◽  
Hengyu Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Liver Cancer ◽  
Critical Role ◽  
Self Renewal ◽  
Sorafenib Treatment ◽  
The Impact

Background. MicroRNAs (miRNAs) play a critical role in the regulation of cancer stem cells (CSCs). However, the role of miRNAs in liver CSCs has not been fully elucidated. Methods. Real-time PCR was used to detect the expression of miR-miR-28-5p in liver cancer stem cells (CSCs). The impact of miR-28-5p on liver CSC expansion was investigated both in vivo and in vitro. The correlation between miR-28-5p expression and sorafenib benefits in HCC was further evaluated in patient-derived xenografts (PDXs). Results. Our data showed that miR-28-5p was downregulated in sorted EpCAM- and CD24-positive liver CSCs. Biofunctional investigations revealed that knockdown miR-28-5p promoted liver CSC self-renewal and tumorigenesis. Consistently, miR-28-5p overexpression inhibited liver CSC’s self-renewal and tumorigenesis. Mechanistically, we found that insulin-like growth factor-1 (IGF-1) was a direct target of miR-28-5p in liver CSCs, and the effects of miR-28-5p on liver CSC’s self-renewal and tumorigenesis were dependent on IGF-1. The correlation between miR-28-5p and IGF-1 was confirmed in human HCC tissues. Furthermore, the miR-28-5p knockdown HCC cells were more sensitive to sorafenib treatment. Analysis of patient-derived xenografts (PDXs) further demonstrated that the miR-28-5p may predict sorafenib benefits in HCC patients. Conclusion. Our findings revealed the crucial role of the miR-28-5p in liver CSC expansion and sorafenib response, rendering miR-28-5p an optimal therapeutic target for HCC.

scholarly journals ZBP-89 negatively regulates self-renewal of liver cancer stem cells via suppression of Notch1 signaling pathway

2020 ◽  
Vol 472 ◽  
pp. 70-80 ◽  
Author(s):  
Nuozhou Wang ◽  
Ming-yue Li ◽  
Yi Liu ◽  
Jianqing Yu ◽  
Jianwei Ren ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Liver Cancer ◽  
Signaling Pathway ◽  
Self Renewal ◽  
Liver Cancer Stem Cells ◽  
Notch1 Signaling ◽  
Notch1 Signaling Pathway

Salinomycin suppresses tumorigenicity of liver cancer stem cells and Wnt/beta-catenin signaling

2020 ◽  
Vol 15 ◽  
Author(s):  
Qiuping Liu ◽  
Jinghui Sun ◽  
Qing Luo ◽  
Yang Ju ◽  
Guanbin Song
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Liver Cancer ◽  
Signaling Pathway ◽  
Chemotherapy Resistance ◽  
Antitumor Agent ◽  
Beta Catenin ◽  
Liver Cancer Stem Cells

Background: Accumulating evidence has revealed the important role of cancer stem cells (CSCs) in driving tumor initiation and tumor relapse or metastasis. Therapeutic strategies that selectively target CSCs may be effective approaches to eliminate cancer. Salinomycin, an antitumor agent, was identified as a selective inhibitor of several types of CSCs. We previously reported that salinomycin inhibits the migration and invasiveness of liver cancer stem cells (LCSCs). Objective: This study was conducted to explore the role of salinomycin in supressing stemness properties of LCSCs and the mechanism. Methods: LCSCs were identified and enriched from MHCC97H cells. Salinomycin was used to treat LCSCs at the indicated concentrations. Sphere formation ability, chemotherapy resistance, expression of CSC surface markers, Young's modulus and tumorigenicity of LCSCs were assessed to evaluate the effect of salionmycin on LCSCs. The expression of β-catenin was evaluated by western blotting. LiCl was used to activate the Wnt/β-catenin signaling pathway. Results: Salinomycin suppresses the stemness properties of LCSCs. Moreover, salinomycin could also inhibit the activation of Wnt/β-catenin signaling in LCSCs. Nevertheless, the stemness properties of LCSCs could be recovered when Wnt/β-catenin signaling was activated by LiCl. Further studies demonstrated that salinomycin also significantly reduces the tumorigenicity of LCSCs in vivo by suppressing the Wnt/β-catenin signaling pathway. Conclusion: Salinomycin could suppress stemness properties and induce differentiation of LCSCs through the Wnt/β-catenin signaling pathway, which provides evidence that salinomycin may serve as a potential drug for liver cancer therapy targeting LCSCs in the clinic.

scholarly journals Clonogenically Culturing and Expanding CD34+ Liver Cancer Stem Cells in Vitro

2015 ◽  
Vol 24 (13) ◽  
pp. 1506-1514 ◽  
Author(s):  
Su Cheol Park ◽  
Changjun Zeng ◽  
Benjamin Tschudy-Seney ◽  
Ngoc Tue Nguyen ◽  
Jong Ryeol Eun ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Liver Cancer ◽  
Liver Cancer Stem Cells

scholarly journals ELK3 promotes the migration and invasion of liver cancer stem cells by targeting HIF-1α

2016 ◽  
Vol 37 (2) ◽  
pp. 813-822 ◽  
Author(s):  
Joon Ho Lee ◽  
Wonhee Hur ◽  
Sung Woo Hong ◽  
Jung-Hee Kim ◽  
Sung Min Kim ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Liver Cancer ◽  
Migration And Invasion ◽  
Liver Cancer Stem Cells

scholarly journals Mutant MEG3 Enhances the Activity of Telomerase by Increasing DNA Damage Repair in Human Liver Cancer Stem Cells

2021 ◽  
Author(s):  
Shuting Song ◽  
Sijie Xie ◽  
Rushi Qin ◽  
Yanan Lu ◽  
Liyan Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Cancer Stem Cells ◽  
Liver Cancer ◽  
Human Liver ◽  
Dna Damage Repair ◽  
Liver Cancer Stem Cells ◽  
Damage Repair ◽  
Human Liver Cancer

Abstract Background: Long noncoding RNAs have recently considered as central regulators in diverse biological processes and emerged as vital players controlling tumorigenesis. Although wild MEG3 acts as a suppressor in several cancers, the function of mutant MEG3 is also unclear during tumorigenesis.Methods: Lentivalus infection,RT-PCR,Western blotting and tumorigenesis test in vitro and in vivo were performed.Results: our results suggest that mutant MEG3 promotes the growth of human liver cancer stem cells in vivo and in vitro.Mechanistically, our results show that mutant MEG3 enhances acetylation modification of HistoneH4 on K16.Then, mutant MEG3 enhances the expression of SETD2 dependent on H4K16Ac.Moreover, mutant MEG3 increases the DNA damage repair through SETD2.Ultimately, mutant MEG3 increases the telomeras activity dependent on DNA damage repair.Strikingly,TERT determines the cancerous function of mutant MEG3 in liver cancer stem cells. Therefore, we shed light on the fact that targeting mutant MEG3 could be a viable approach for cancer treatment.Conclusions: these observations will play an important role in finding effective tumor treatment targets.

scholarly journals Inhibitory Effects of LOXL2 Knockdown On Cellular Functions of Liver Cancer Stem Cells

2021 ◽  
Author(s):  
Na Li ◽  
Huan Gu ◽  
Liu Liu ◽  
Xiao Li Zhang ◽  
Qiu Luo Cheng ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Liver Cancer ◽  
Lysyl Oxidase ◽  
Migration And Invasion ◽  
Mrna Levels ◽  
Spheroid Formation ◽  
Liver Cancer Stem Cells ◽  
Hep3b Cells

Abstract Background and aim: Lysyl oxidase-like 2 (LOXL2) plays a role in tumor microenvironment formation and metastasis of hepatocellular carcinoma (HCC), which has a high mortality burden. Liver cancer stem cells (LCSCs) are related with the major malignant phenotypes of HCC. The function of LOXL2 in regulation of LCSCs remains unknown.Methods: CD133+HepG2 and CD133+Hep3B cells were sorted by fluorescence-activated cell sorting (FACS) from two human hepatoblastoma cell lines. Spheroid formation, apoptosis, cell cycle, as well as transwell assays were performed upon LOXL2 knock down in CD133+HepG2 and CD133+Hep3B cells. Protein and mRNA levels were quantified by Western blotting, Immunofluorescence and real-time PCR. Results: Knockdown of LOXL2 decreased spheroid formation, migration and invasion (p < 0.05), also induced apoptosis (p < 0.05) and cell cycle arrest (p < 0.05) in CD133+HepG2 and CD133+Hep3B cells. Knockdown of LOXL2 effectively inhibited expression of the anti-apoptosis proteins baculoviral IAP repeat-containing 3 (BIRC3) and murine double minute 2 (MDM2) (p < 0.01), as well as autophagy marker microtubule-associated protein 1 light chain 3 B (LC3) and autophagy gene ATG5 in CD133+HepG2 and CD133+Hep3B cells (p < 0.01). Conclusions: The results revealed that LOXL2 inhibition could reduce the proliferation and expansion of LCSCs, making LOXL2 inhibitors an attractive and novel therapeutic strategy of HCC.

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